title: Chemotherapy of skull base chordoma tailored on responsiveness of patient-derived tumor cells to rapamycin.
abstract: Skull base chordomas are challenging tumors due to their deep surgical location and resistance to conventional radiotherapy. Chemotherapy plays a marginal role in the treatment of chordoma resulting from lack of preclinical models due to the difficulty in establishing tumor cell lines and valuable in vivo models. Here, we established a cell line from a recurrent clival chordoma. Cells were cultured for more than 30 passages and the expression of the chordoma cell marker brachyury was monitored using both immunohistochemistry and Western blot. Sensitivity of chordoma cells to the inhibition of specific signaling pathways was assessed through testing of a commercially available small molecule kinase inhibitor library. In vivo tumorigenicity was evaluated by grafting chordoma cells onto immunocompromised mice and established tumor xenografts were treated with rapamycin. Rapamycin was administered to the donor patient and its efficacy was assessed on follow-up neuroimaging. Chordoma cells maintained brachyury expression at late passages and generated xenografts closely mimicking the histology and phenotype of the parental tumor. Rapamycin was identified as an inhibitor of chordoma cell proliferation. Molecular analyses on tumor cells showed activation of the mammalian target of rapamycin signaling pathway and mutation of KRAS gene. Rapamycin was also effective in reducing the growth of chordoma xenografts. On the basis of these results, our patient received rapamycin therapy with about six-fold reduction of the tumor growth rate upon 10-month follow-up neuroimaging. This is the first case of chordoma in whom chemotherapy was tailored on the basis of the sensitivity of patient-derived tumor cells.
authors.affiliation: Department of Haematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Ricci-Vitiani
authors.forename: Daniele
authors.initials: D
authors.lastname: Runci
authors.forename: Quintino Giorgio
authors.initials: QG
authors.lastname: D'Alessandris
authors.forename: Tonia
authors.initials: T
authors.lastname: Cenci
authors.forename: Maurizio
authors.initials: M
authors.lastname: Martini
authors.forename: Federico
authors.initials: F
authors.lastname: Bianchi
authors.forename: Giulio
authors.initials: G
authors.lastname: Maira
authors.forename: Louis
authors.initials: L
authors.lastname: Stancato
authors.forename: Ruggero
authors.initials: R
authors.lastname: De Maria
authors.forename: Luigi Maria
authors.initials: LM
authors.lastname: Larocca
authors.forename: Roberto
authors.initials: R
authors.lastname: Pallini
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002817:Chordoma / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D009154:Mutation; D061251:Primary Cell Culture; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D020123:Sirolimus / Q000494:pharmacology* / Q000627:therapeutic use; D019292:Skull Base Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D020123:Sirolimus